The present invention relates to a method and pharmaceutical formulation for treating a patient who is resistant to the antihypertensive effect of an antihypertensive compound in absence of melatonin, a method for lowering nocturnal blood pressure in patients who have an abnormal rhythm in blood pressure in the absence or presence of an antihypertensive compound, a method for lowering cortisol levels and protecting from cardiovascular events, and use of melatonin in the manufacture of medicaments for the stated purposes.
There is a daily variation in blood pressure (circadian blood pressure rhythm) which is characterized by a nocturnal fall and a diurnal rise. The normal pattern of circadian blood pressure rhythm is reversed in elderly people and in those with Cushing's syndrome, those undergoing glucocorticoid treatment, and those with hyperthyroidism, central and/or peripheral autonomic dysfunction (Shy-Drager syndrome, tetraplegia, diabetic or uremic neuropathy etc.), chronic renal failure, renal or cardiac transplantation, congestive heart failure, eclampsia, sleep apnea syndrome, malignant hypertension, systemic atherosclerosis, accelerated hypertensive organ damage (Imai, Abe et al. Journal of hypertension (supplement) 8:S125-132, 1990) and fatal familial insomnia (Portaluppi, Cortelli et al. Hypertension 23:569-576, 1994). A less-than-normal decline in nocturnal blood pressure is seen in some hypertensive patients despite treatment with antihypertensive drugs. A less-than-normal decline in nocturnal blood pressure has been associated with excessive cardiovascular complications in hypertensive patients. Patients with impaired nocturnal blood pressure reduction (nondippers) are at increased risk of developing target organ damage (1-4) and nondipper women have been shown to develop more cardiovascular events (5) than their dipper counterparts. The mechanism of the normal fall of blood pressure during sleep and the pathophysiological mechanisms responsible for lack of nocturnal fall in blood pressure remain to be fully elucidated.
Glucocorticoid hormones play a critical role in a variety of bodily functions. In the basal state, glucocorticoids exert a permissive effect on diverse body functions such as maintenance of blood pressure, euglycemia, and electrolyte and water hemostasis. In humans, cortisol is essential for life. Normally, cortisol secretion from the adrenal gland is rhythmic, with maximal blood levels in the early morning hours, and a decline to half of the peak value in the afternoon. During stress, excretion of cortisol is greatly increased to cope with serious whole body insult. However, sustained elevation of cortisol in circulation has detrimental effects on the immune system and on the ability of the body to cope with stress and disease. Most importantly, corticosteroids can provoke a neurodegenerative process in the hippocampus leading to impaired memory and cognitive functions. Prolonged exposure of the brain to corticosteroids makes it more vulnerable to degeneration induced by ischemia and epilepsy (McEwen, Annals of the New York Academy of Science, 1994, 746: 145-154). With aging, the basal secretion of cortisol increases by unknown mechanisms and its peak occurs earlier in the morning than in young adults (Moreley and Korenman, eds., Blackwell Scientific Publications, 1992, pp 70-91). In addition, nocturnal cortisol levels have been found to be higher in coronary patients than aged-matched healthy subjects (Brugger and Herold, Biological Rhythm Research, 1995, 26: 373). There is an association between hypertension and high urine cortisol values (Lichtenfeld, Hunt et al, Hypertension, 31:569-74, 1998), oral cortisol increases blood pressure in a dose dependent manner (Kelly, Mangos et al, Clin Exp Pharmacol Physiol Suppl 25:S51-6, 1998). It has not been previously suggested that there is an association between the high cortisol levels and the absence of nocturnal dip in blood pressure.
Melatonin, the hormone secreted at night from the pineal gland, reaches its peak levels before the onset of the cortisol peak in humans. The production of melatonin declines with age. Also, nocturnal melatonin levels are lower in coronary patients than in healthy aged-matched individuals. However, it has not been suggested that melatonin affects cortisol secretion under normal conditions.